A novel TBX20 loss-of-function mutation contributes to adult-onset dilated cardiomyopathy or congenital atrial septal defect

被引:28
作者
Zhou, Yi-Meng [1 ]
Dai, Xiao-Yong [1 ]
Huang, Ri-Tai [2 ]
Xue, Song [2 ]
Xu, Ying-Jia [3 ]
Qiu, Xing-Biao [3 ]
Yang, Yi-Qing [3 ,4 ,5 ]
机构
[1] Tongji Univ, Sch Med, Yangpu Hosp, Dept Emergency Med, 450 Tengyue Rd, Shanghai 200090, Peoples R China
[2] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Cardiovasc Surg, Shanghai 200127, Peoples R China
[3] Shanghai Jiao Tong Univ, Shanghai Chest Hosp, Dept Cardiol, Shanghai 200030, Peoples R China
[4] Shanghai Jiao Tong Univ, Shanghai Chest Hosp, Dept Cardiovasc Res Lab, 241 West Huaihai Rd, Shanghai 200030, Peoples R China
[5] Shanghai Jiao Tong Univ, Shanghai Chest Hosp, Cent Lab, Shanghai 200030, Peoples R China
基金
中国国家自然科学基金;
关键词
dilated cardiomyopathy; genetics; transcriptional factor; TBX20; reporter gene assay; HOLT-ORAM-SYNDROME; HEART-DISEASE; TRANSCRIPTION FACTORS; SPORADIC TETRALOGY; GATA5; GENE; NKX2-5; SPECTRUM; IDENTIFICATION; PREVALENCE;
D O I
10.3892/mmr.2016.5609
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Dilated cardiomyopathy (DCM) is the most prevalent form of primary cardiomyopathy in humans and is a leading cause of heart failure and sudden cardiac death. Genetic abnormalities have been demonstrated to be a major contributor to the development of DCM. However, DCM is a genetically heterogeneous disease, and the genetic basis underlying DCM in a significant proportion of patients remains unclear. In the current study, the coding exons and splicing junction sites of the T-Box 20 (TBX20) gene, which encodes a T-box transcription factor essential for cardiac morphogenesis and structural remodeling, were sequenced in 115 unrelated patients with idiopathic DCM, and a novel heterozygous mutation, p.E143X, was identified in one patient. Genetic analysis of the mutation carrier's pedigree indicated that the nonsense mutation was present in all the living family members with DCM, and also in a female patient with a congenital atrial septal defect. The mutation, which was predicted to generate a truncated protein with only the N-terminus and a fraction of the T-box domain remaining, was absent in 800 control chromosomes. Functional assays using a dual-luciferase reporter assay system revealed that the truncated TBX20 protein had no transcriptional activity in contrast to its wild-type counterpart. Furthermore, the mutation abolished the synergistic activation between TBX20 and NK2 homeobox 5, or between TBX20 and GATA binding protein 4. The observations of the current study expand the mutation spectrum of TBX20 associated with DCM and congenital heart disease (CHD), which provide novel insight into the molecular mechanisms underlying DCM and CHD, suggesting the potential implications for the effective and personalized treatment of these diseases.
引用
收藏
页码:3307 / 3314
页数:8
相关论文
共 61 条
  • [1] SPEG Interacts with Myotubularin, and Its Deficiency Causes Centronuclear Myopathy with Dilated Cardiomyopathy
    Agrawal, Pankaj B.
    Pierson, Christopher R.
    Joshi, Mugdha
    Liu, Xiaoli
    Ravenscroft, Gianina
    Moghadaszadeh, Behzad
    Talabere, Tiffany
    Viola, Marissa
    Swanson, Lindsay C.
    Haliloglu, Goknur
    Talim, Beril
    Yau, Kyle S.
    Allcock, Richard J. N.
    Laing, Nigel G.
    Perrella, Mark A.
    Beggs, Alan H.
    [J]. AMERICAN JOURNAL OF HUMAN GENETICS, 2014, 95 (02) : 218 - 226
  • [2] Cardiac transcription factor Csx/Nkx2-5: its role in cardiac development and diseases
    Akazawa, H
    Komuro, I
    [J]. PHARMACOLOGY & THERAPEUTICS, 2005, 107 (02) : 252 - 268
  • [3] Molecular basis of the clinical features of Holt-Oram syndrome resulting from missense and extended protein mutations of the TBX5 gene as well as TBX5 intragenic duplications
    Al-Qattan, Mohammad M.
    Abou Al-Shaar, Hussam
    [J]. GENE, 2015, 560 (02) : 129 - 136
  • [4] Of mice and men: molecular genetics of congenital heart disease
    Andersen, Troels Askhoj
    Troelsen, Karin de Linde Lind
    Larsen, Lars Allan
    [J]. CELLULAR AND MOLECULAR LIFE SCIENCES, 2014, 71 (08) : 1327 - 1352
  • [5] Fine Mapping of the 1p36 Deletion Syndrome Identifies Mutation of PRDM16 as a Cause of Cardiomyopathy
    Arndt, Anne-Karin
    Schafer, Sebastian
    Drenckhahn, Jorg-Detlef
    Sabeh, M. Khaled
    Plovie, Eva R.
    Caliebe, Almuth
    Klopocki, Eva
    Musso, Gabriel
    Werdich, Andreas A.
    Kalwa, Hermann
    Heinig, Matthias
    Padera, Robert F.
    Wassilew, Katharina
    Bluhm, Julia
    Harnack, Christine
    Martitz, Janine
    Barton, Paul J.
    Greutmann, Matthias
    Berger, Felix
    Hubner, Norbert
    Siebert, Reiner
    Kramer, Hans-Heiner
    Cook, Stuart A.
    MacRae, Calum A.
    Klaassen, Sabine
    [J]. AMERICAN JOURNAL OF HUMAN GENETICS, 2013, 93 (01) : 67 - 77
  • [6] Identification of TBX5 Mutations in a Series of 94 Patients With Tetralogy of Fallot
    Baban, Anwar
    Postma, Alex Vincent
    Marini, Monica
    Trocchio, Gianluca
    Santilli, Antonella
    Pelegrini, Monica
    Sirleto, Pietro
    Lerone, Margherita
    Albanese, Sonia Bernadette
    Barnett, Phil
    Boogerd, Cornelis Job
    Dallapiccola, Bruno
    Digilio, Maria Cristina
    Ravazzolo, Roberto
    Pongiglione, Giacomo
    [J]. AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2014, 164 (12) : 3100 - 3107
  • [7] A novel mutation of the LMNA gene in a family with dilated cardiomyopathy, conduction system disease, and sudden cardiac death of young females
    Chen, Wenting
    Huo, Jianhua
    Ma, Aiqun
    Bai, Ling
    Liu, Ping
    [J]. MOLECULAR AND CELLULAR BIOCHEMISTRY, 2013, 382 (1-2) : 307 - 311
  • [8] Functional Characterization of a Novel Mutation in NKX2-5 Associated With Congenital Heart Disease and Adult-Onset Cardiomyopathy
    Costa, Mauro W.
    Guo, Guanglan
    Wolstein, Orit
    Vale, Molly
    Castro, Maria L.
    Wang, Libin
    Otway, Robyn
    Riek, Peter
    Cochrane, Natalie
    Furtado, Milena
    Semsarian, Christopher
    Weintraub, Robert G.
    Yeoh, Thomas
    Hayward, Christopher
    Keogh, Anne
    Macdonald, Peter
    Feneley, Michael
    Graham, Robert M.
    Seidman, Jonathan G.
    Seidman, Christine E.
    Rosenthal, Nadia
    Fatkin, Diane
    Harvey, Richard P.
    [J]. CIRCULATION-CARDIOVASCULAR GENETICS, 2013, 6 (03) : 238 - 247
  • [9] Novel Mutations in the Transcriptional Activator Domain of the Human TBX20 in Patients with Atrial Septal Defect
    Eloisa Monroy-Munoz, Irma
    Perez-Hernandez, Nonanzit
    Manuel Rodriguez-Perez, Jose
    Esteban Munoz-Medina, Jose
    Angeles-Martinez, Javier
    Garcia-Trejo, Jose J.
    Morales-Ríos, Edgar
    Masso, Felipe
    Pablo Sandoval-Jones, Juan
    Cervantes-Salazar, Jorge
    Antonio Garcia-Montes, Jose
    Calderon-Colmenero, Juan
    Vargas-Alarcon, Gilberto
    [J]. BIOMED RESEARCH INTERNATIONAL, 2015, 2015
  • [10] The genetics of dilated cardiomyopathy
    Flack, English
    Kannankeril, Prince J.
    [J]. HEART RHYTHM, 2012, 9 (03) : 397 - 398